Risk Minimisation Measures (RMMs): overview and effectiveness

Designing a risk minimisation measure is the easy part. Proving it actually works is where most organisations struggle. 

That was the starting point of our recent webinar, Risk Minimisation Measures, where we looked at how RMMs fit into the lifecycle of a Risk Management Plan, from the routine measures included in every product’s information to the additional tools designed for specific safety concerns, such as educational materials, controlled access schemes or pregnancy prevention initiatives. 

This article expands on those themes in more depth. We walk through the different types of RMMs, how Marketing Authorisation Holders and regulatory authorities share responsibility for getting them right, and why measuring their real-world effectiveness is just as important as choosing the right measure in the first place. 

RMMs are a crucial tool to prevent or reduce the occurrence of an adverse reaction associated with medication, or to reduce its severity if the reaction does occur. These activities are part of the risk management system outlined in the Risk Management Plan (RMP), helping to maintain a favorable benefit-risk balance throughout the drug’s lifecycle. In fact, RMMs can be defined at the moment of the marketing authorization application (sometimes the introduction of an RMM can be a condition for the granting of the marketing authorization) or they can be implemented in the post-marketing phase arising from EMA procedures (signals, referral, PSUSA etc) or from the marketing authorization itself.  

For the RMMs management, the RMP plays a central role, as it is the document that describes, in the relevant sections, the known and potential risks associated with the medicinal product and the action taken to mitigate them. 

The RMMs were defined according to the critical issues identified during both the pre-marketing and post-marketing phases. They are divided into two categories, routine RMMs (rRMM) and additional RMMs (aRMM). 

rRMMs  

Applies to all medicinal products independently from the presence of identified risk: 

• SmPC_ Information about adverse events, warnings, and drug use, as well as any references to aRMMs for healthcare professionals. 

• PIL_ Information about adverse events, warnings, and drug use, as well as any references to aRMMs for patients. 

• Packaging_ It may include specific warnings or pictograms. 

• Legal status_ Prescription, limited prescription etc. 

• Pack size_ Appropriate amount for the treatment course, in order to prevent abuse or misuse 

aRMMs  

Are implemented when routine risk minimization measures alone are not sufficient to manage the specific risks associated with a drug. They can be divided into educational materials and other tools. 

• Educational materials 

• HCP/Patients guide_ Information for healthcare professionals and patients on risks, how to recognize them, and how to manage them. 

• Healthcare Professional training material_ Product guides for the drug utilization for heathcare professionals. 

• Checklist_ List of information for physicians to ensure proper prescribing. 

• Patient alert card_ Additional information included in the packaging of the medicinal product that provides specific guidance on the risk 

The content, format and tools (paper, video, webinar etc.) for all these educational materials should be agreed with the national competent authority. In addition, in order to facilitate the use and observation of these measures, all marketing authorization holders (MAHs) were encouraged to collaborate to make the material as similar and consistent as possible. 

• Other tools 

These measures are intended for application in one or more healthcare settings, depending on whether the required control concerns the steps of prescribing, distribution, dispensing and/or administration of the medicinal product. 

• Controlled access programmes 

Measures aimed at controlling access to a medicinal product beyond the controls provided by rRMM (e.g., legal status): 

• Patient-specific tests and/or examinations to ensure compliance with clinical criteria 

• Procedures for the systematic follow-up of patients through enrollment in a specific data collection system (e.g., registries) 

• Medicines dispensed exclusively by authorized pharmacies (e.g., hospital pharmacies) 

• Controlled distribution systems  

A set of measures implemented to ensure the traceability of the various stages of a medicine’s distribution chain, all the way back to the prescribing physician and/or the pharmacy that dispenses it. 

• Pregnancy prevention programmes (PPP) 

A set of measures implemented to promote the safe use of medications during pregnancy. These are adopted in case of high drug toxicity for the fetus (e.g. retinoids teratogenicity). Specifically, they usually include healthcare professional and patient educational materials, checklist for physicians, specific test to be performed before the drug prescription by physicians and drug dispensation by pharmacists.

A DHPC is a safety communication tool that can be required to support the dissemination of aRMM, in particular when launching a new or amended additional RMM for a medicinal product. 

It can be also used to communicate new safety information that is not necessarily related to an additional risk mitigation measure: 

• Significant change in the use of a medicinal product due to a restriction of an indication, a new contraindication, or a change in the recommended dose for safety reasons; 

• New important warnings or precautions to be included in the product information; 

• New data highlighting a previously unknown risk or a change in the frequency or severity of a known risk; 

• New recommendations for the prevention or treatment of adverse reactions or to prevent misuse or medication errors with the medicine. 

Continuous and accurate evaluation is as important as the appropriate selection and implementation of an aRMM. The evaluation plan of the aRMM is described in the relevant part of RMPs. The efficacy assessment is based on various types of indicators: 

Process indicators make it possible to verify whether measures have been properly implemented and include, for example, reaching the target population, assessing the clinical knowledge of healthcare professionals through surveys, and analyzing prescribing practices through drug utilization studies.  

Outcome indicators, on the other hand, allow for the assessment of the actual impact of RMMs on patient safety by analyzing the frequency and/or severity of adverse reactions in relation to exposure to the drug in real-world clinical practice. 

In the context of RMM, the European health authority, as well as all the national authorities, play a central role in protecting public health by mandating, approving, and evaluating these measures. In fact, regardless of whether the need to implement an aRMM comes from the authority or from a MAH, the choice, the content, the dissemination, the implementation and the evaluation of the efficacy is agreed between the MAH(s) and the authority. 

Based on the risk and the product, the chosen risk minimization measure can be imposed by the authority either to a specific MAH in a specific country or to all MAHs of the same active substance in all countries. Considering that each member state may have different national legal requirements and local healthcare systems every aRMM, even if requested for all MAHs, must be finally approved by the national authority.  

Taking into account what is retrieved by MAH(s) during the pharmacovigilance activities, the authority must assess the efficacy of the RMM. Based on this evaluation, it can be concluded either that the activity is effective or ineffective, leading respectively to their continued implementation or to their modification and/or reinforcement. 

In conclusion, RMMs represent a fundamental tool in ensuring the safe and effective use of medicinal products throughout their lifecycle. The collaborative role between MAHs and regulatory authorities at both European and national levels ensures that RMMs are appropriately designed, implemented, and adapted to different healthcare settings. This dynamic and evidence-based approach is essential to maintaining a favorable benefit-risk balance and safeguarding public health. 

• Implementing Regulation (EU) 520/2012 

• Implementing Regulation (EU) 2025/1466 

• GVP module V «Risk management system» 

• GVP module XV «Safety communication» 

• GVP module XVI «Risk minimization measures»